Sobetirome in the treatment of myelination diseases

ABSTRACT

Methods of treating a subject having or at risk of developing a neurodegenerative disease or condition associated with demyelination, insufficient myelination, or underdevelopment of myelin sheath are described. The methods include administration of a therapeutically effective amount of sobetirome, or a pharmaceutically acceptable salt thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a continuation of U.S. application Ser. No. 16/275,117, filedFeb. 13, 2019, which is the continuation of U.S. application Ser. No.14/888,577, filed Nov. 2, 2015, issued as U.S. Pat. No. 10,226,438 onMar. 12, 2019, which is the U.S. National Stage of InternationalApplication No. PCT/US2014/014943, filed Feb. 5, 2014, published inEnglish under PCT Article 21(2), which is a continuation-in-part ofInternational Application No. PCT/US2013/053640, filed on Aug. 5, 2013.International Application Nos. PCT/US2014/014943 and PCT/US2013/053640both claim the benefit of U.S. Provisional Application 61/819,467, filedon May 3, 2013. The disclosures of each of the above applications areincorporated herein by reference.

ACKNOWLEDGMENT OF GOVERNMENT SUPPORT

This invention was made with government support under grant numberDK-52798 awarded by the National Institutes of Health. The governmenthas certain rights in the invention.

PARTIES TO JOINT RESEARCH AGREEMENT

The inventions described in this application were made by Oregon Health& Sciences University and The United States Government as represented bythe Department of Veterans Affairs as a result of activities undertakenwithin the scope of a joint research agreement.

FIELD

This disclosure concerns methods for the treatment of diseases orconditions associated with demyelination, insufficient myelination orunderdevelopment of the myelin sheath. This disclosure further relatesto the use of sobetirome for the treatment of such diseases andconditions.

BACKGROUND

Oligodendrocytes (OL) generate and maintain myelin in the centralnervous system (CNS). During development, oligodendrocyte precursorcells (OPC) differentiate into OL and this differentiation step dependson the thyroid hormone, triiodothyronine (T3). Following demyelination,remyelination may involve T3-dependent differentiation of OPC into OL,which depends on transcription factors, e.g., Kruppel-like factor 9(Klf9). Currently available treatments of demyelinating diseases arelimited in their efficacy. For some demyelinating diseases, there are noknown treatments available. Thus, therapeutic agents capable ofpromoting remyelination, without toxic side effects, represent an unmetmedical need.

SUMMARY

The present disclosure features the use of a CNS active, non-cardiotoxicdrug (sobetirome) capable of reducing demyelination and promotingmyelination without causing thyrotoxicosis. Sobetirome, andpharmaceutically acceptable salts thereof, provide a viable treatmentfor preventing and reversing demyelination in disorders such as multiplesclerosis (MS) and other diseases or conditions associated withdemyelination, insufficient myelination, or underdevelopment of themyelin sheath.

Methods of treating a subject having or at risk of developing aneurodegenerative disease or condition associated with demyelination,insufficient myelination, or underdevelopment of myelin sheath aredescribed herein. The methods include administration of atherapeutically effective amount of sobetirome, or a pharmaceuticallyacceptable salt thereof.

The foregoing and other objects, features, and advantages of theinvention will become more apparent from the following detaileddescription, which proceeds with reference to the accompanying figures.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: Sobetirome reduced demyelination in the corpus callosum of micefollowing injection of lysolecithin. Top, BlackGold® stain is specificfor myelin fibers and cresyl violet is used as a counterstain. Micereceived stereotactic injections of 2 μL of PBS or 2% lysolecithin inthe corpus callosum. A white arrow indicates the path of the injectionneedle and a black box indicates the lesion site. An enlarged image ofthe boxed lesion site is shown to the right. Bottom, brain sections of30 μm were stained with FluoroMyelin™, anti-PDGFR-α and DAPI.Hypothyroidism was induced with drinking water treatment, and bothhypothyroid and control mice received vehicle injections. T3 (0.4 mg/kg)and sobetirome (1 mg/kg) were administered by daily i.p. injectionsstarting 7 days before stereotactic injection of lysolecithin. Mice wereeuthanized 8 days after stereotactic injection of 2% lysolecithin, andbrains were harvested and processed for histological analysis.

FIG. 2: Sobetirome reduces demyelination in mice with EAE. The dot plotdisplays the mean percentage area of damage in the ventrolateral whitematter of C57BL/6 mice after 11 days of treatment with sobetirome andvehicle. EAE was induced in female mice with MOG 35-55 peptide. On day17 post immunization, mice were randomized based on their EAE scores anddaily i.p. injections of sobetirome (n=8) or vehicle (n=8) were started.Mice were euthanized after 11 days of treatment and spinal cords wereprepared for histological evaluation. The mean percentage ofventrolateral demyelination for vehicle treated mice was 17.25(SD+/−7.09) and 9.11 (SD+/−4.96) for sobetirome (p<0.01).

FIGS. 3A-3D: Sobetirome prevents demyelination and axonal loss.Representative Black gold II (FIGS. 3A-3B) and toluidine blue (FIGS.3B-3C) images from lumbar and thoracic EAE ventral spinal cordrespectively. Sobetirome treated (FIGS. 3A and 3C) and vehicle (FIGS. 3Band 3D). Demyelination is clearly visible in a vehicle-treated mouse butnot in a sobetirome-treated mouse. Arrows show unstable myelin;arrowheads show degenerating axon. Scale bar=20 microns.

DETAILED DESCRIPTION I. Abbreviations

-   -   ADEM acute disseminated encephalomyelitis    -   AIDP acute inflammatory demyelinating polyneuropathy    -   CIDP chronic inflammatory demyelinating polyneuropathy    -   CNS central nervous system    -   EAE experimental autoimmune encephalitis    -   IIDD idiopathic inflammatory demyelinating disease    -   i.p. intraperitoneal    -   MOG myelin oligodendrocyte glycoprotein    -   MS multiple sclerosis    -   NMO neuromyelitis optica    -   OL oligodendrocytes    -   OPC oligodendrocyte precursor cells    -   PML progressive multifocal leukoencephalopathy    -   T3 triiodothyronine    -   X-ALD X-linked adrenoleukodystrophy

II. Terms and Methods

Unless otherwise noted, technical terms are used according toconventional usage. Definitions of common terms in molecular biology maybe found in Benjamin Lewin, Genes V, published by Oxford UniversityPress, 1994 (ISBN 0-19-854287-9); Kendrew et al. (eds.), TheEncyclopedia of Molecular Biology, published by Blackwell Science Ltd.,1994 (ISBN 0-632-02182-9); and Robert A. Meyers (ed.), Molecular Biologyand Biotechnology: a Comprehensive Desk Reference, published by VCHPublishers, Inc., 1995 (ISBN 1-56081-569-8).

In order to facilitate review of the various embodiments of thedisclosure, the following explanations of specific terms are provided:

Acute disseminated encephalomyelitis (ADEM): An immune-mediateddemyelinating disease of the central nervous system. ADEM usually occursfollowing a viral infection, but may also appear following vaccinationor following bacterial or parasitic infection. In some cases, ADEMdevelops spontaneously. The disease involves autoimmune demyelination,similar to multiple sclerosis, and is therefore considered a multiplesclerosis borderline disease. ADEM produces multiple inflammatorylesions in the brain and spinal cord, particularly in the white matter.The lesions are typically found in the subcortical and central whitematter and cortical gray-white junction of both cerebral hemispheres,cerebellum, brainstem, and spinal cord, but periventricular white matterand gray matter of the cortex, thalami and basal ganglia may also beinvolved. When a patient suffers more than one demyelinating episode,the disease is referred to as recurrent disseminated encephalomyelitisor multiphasic disseminated encephalomyelitis.

Acute hemorrhagic leukoencephalitis (AHL or AHLE): A hyperacute andfrequently fatal form of ADEM. This disease is also known as acutenecrotizing encephalopathy (ANE), acute hemorrhagic encephalomyelitis(AHEM), acute necrotizing hemorrhagic leukoencephalitis (ANHLE),Weston-Hurst syndrome, or Hurst's disease.

Administration: To provide or give a subject an agent, such as atherapeutic agent (e.g. sobetirome or a pharmaceutically acceptable saltthereof), by any effective route. Exemplary routes of administration aredescribed hereinbelow.

Adult Refsum disease: An autosomal recessive neurological disease thatis associated with the over-accumulation of phytanic acid in cells andtissues. Adult Refsum disease is divided into the adult Refsum disease 1and adult Refsum disease 2 subtypes. Individuals with Refsum diseasepresent with neurologic damage, cerebellar degeneration, and peripheralneuropathy. Onset is most commonly in childhood/adolescence with aprogressive course, although periods of stagnation or remission occur.Symptoms also include ataxia, scaly skin (ichthyosis), difficultyhearing, and eye problems including cataracts and night blindness.

Alexander disease: A very rare, congenital demyelinating disease. Thedisease primarily affects infants and children, causing developmentaldelay and changes in physical characteristics. Alexander disease is atype of leukodystrophy.

Alzheimer's disease: The most common form of dementia. Symptoms ofAlzheimer's disease include memory loss, confusion, irritability,aggression, mood swings and trouble with language. This disease ischaracterized by the loss of neurons and synapses in the cerebral cortexand certain subcortical regions. The loss results in gross atrophy ofthe affected regions, including degeneration in the temporal lobe, andparts of the frontal cortex and cingulate gyrus. Amyloid plaques andneurofibrillary tangles are visible by microscopy in brains of thoseafflicted with this disease. The cause of Alzheimer's disease isunknown; however, several hypothesis exist, including that the diseaseis caused by age-related myelin breakdown in the brain.

Balo concentric sclerosis: A demyelinating disease similar to standardmultiple sclerosis, but with the particularity that the demyelinatedtissues form concentric layers. Patients with this disease can surviveand/or have spontaneous remission. Typically, the clinical course isprimary progressive, but a relapsing-remitting course has been reported.

Canavan disease: An autosomal recessive degenerative disorder thatcauses progressive damage to nerve cells in the brain. Canavan diseaseis a leukodystrophy and is one of the most common degenerative cerebraldiseases of infancy. This disease is also called Canavan-VanBogaert-Bertrand disease, aspartoacylase deficiency and aminoacylase 2deficiency.

Central pontine myelinolysis (CPM): A neurologic disease caused bysevere damage of the myelin sheath of nerve cells in the brainstem, moreprecisely in the area termed the pons. The most common cause is therapid correction of low blood sodium levels (hyponatremia). Frequentlyobserved symptoms in this disorder are sudden para or quadraparesis,dysphagia, dysarthria, diplopia and loss of consciousness. The patientmay experience locked-in syndrome where cognitive function is intact,but all muscles are paralyzed with the exception of eye blinking.

Cerebral palsy: A term used for a group of permanent, non-progressivemovement disorders that cause physical disability. Cerebral palsy iscaused by damage to the motor control centers of the developing brainand can occur during pregnancy, during childbirth, or after birth up toabout age three. Patients with cerebral palsy exhibit damage to myelinsheaths.

Cerebrotendineous xanthomatosis: An inherited disorder associated withthe deposition of a form of cholesterol (cholestanol) in the brain andother tissues and with elevated levels of cholesterol in plasma but withnormal total cholesterol level. It is characterized by progressivecerebellar ataxia beginning after puberty and by juvenile cataracts,juvenile or infantile onset chronic diarrhea, childhood neurologicaldeficit, and tendineous or tuberous xanthomas. This disorder is anautosomal recessive form of xanthomatosis. It falls within a group ofgenetic disorders called the leukodystrophies.

Chronic inflammatory demyelinating polyneuropathy (CIDP): An acquiredimmune-mediated inflammatory disorder of the peripheral nervous system.The disorder is sometimes called chronic relapsing polyneuropathy (CRP)or chronic inflammatory demyelinating polyradiculoneuropathy (because itinvolves the nerve roots). CIDP is closely related to Guillain-Barrésyndrome and it is considered the chronic counterpart of that acutedisease. Its symptoms are also similar to progressive inflammatoryneuropathy. An asymmetrical variant of CIDP is known as Lewis-Sumnersyndrome. The pathologic hallmark of the disease is loss of the myelinsheath.

Demyelinating disease: Includes any disease of the nervous system inwhich myelin is damaged or lost, or in which the growth or developmentof the myelin sheath is impaired. Demyelination inhibits the conductionof signals in the affected nerves, causing impairment in sensation,movement, cognition, or other functions for which nerves are involved.Demyelinating diseases have a number of different causes and can behereditary or acquired. In some cases, a demyelinating disease is causedby an infectious agent, an autoimmune response, a toxic agent ortraumatic injury. In other cases, the cause of the demyelinating diseaseis unknown (“idiopathic”) or develops from a combination of factors.

Devic's syndrome: An autoimmune, inflammatory disorder in which aperson's immune system attacks the optic nerves and spinal cord, whichresults in inflammation of the optic nerve (optic neuritis) and thespinal cord (myelitis). Spinal cord lesions lead to varying degrees ofweakness or paralysis in the legs or arms, loss of sensation, and/orbladder and bowel dysfunction. Although inflammation may also affect thebrain, the lesions are different from those observed in MS. Devic'sdisease is similar to MS in that the body's immune system attacks themyelin surrounding nerve cells. Unlike standard MS, the attacks are notbelieved to be mediated by the immune system's T cells but rather byantibodies called NMO-IgG. These antibodies target a protein calledaquaporin 4 in the cell membranes of astrocytes which acts as a channelfor the transport of water across the cell membrane. Devic's syndrome isalso known as Devic's disease or neuromyelitis optica (NMO).

Diffuse myelinoclastic sclerosis: An uncommon neurodegenerative diseasethat presents clinically as pseudotumoral demyelinating lesions. Itusually begins in childhood, affecting children between 5 and 14 yearsold; however, cases in adults are possible. This disease is consideredone of the borderline forms of MS and is sometimes referred to asSchilder's disease.

Encephalomyelitis: Inflammation of the brain and spinal cord.

Experimental autoimmune encephalomyelitis (EAE): An animal model of MS(for example, see Gold et al., Brain 129:1953-1971, 2006). EAE animalsexhibit characteristic plaques of tissue injury disseminated throughoutthe central nervous system. Plaques show infiltration of nervous tissueby lymphocytes, plasma cells, and macrophages, which cause destructionof the myelin sheaths that surround nerve cell axons in the brain andspinal cord. In some cases, EAE is induced by immunization ofsusceptible animals, such as mice, rats, guinea pigs, or non-humanprimates, with either myelin or various components of myelin. Forexample, EAE can be induced by immunization with components of themyelin sheath, such as myelin basic protein, proteolipid protein, ormyelin oligodendrocyte glycoprotein (MOG). EAE is a useful and widelyaccepted model for studying mechanisms of autoimmune CNS tissue injuryand for testing potential therapies for MS. EAE also includes “passiveEAE” which is induced in the same manner in donor animals, but involvesthe transfer of activated T-cells harvested from the donor animal'slymph nodes to naïve recipient animals.

Guillain-Barré syndrome: An acute polyneuropathy, a disorder affectingthe peripheral nervous system. Ascending paralysis, weakness beginningin the feet and hands and migrating towards the trunk, is the mosttypical symptom, and some subtypes cause change in sensation or pain, aswell as dysfunction of the autonomic nervous system. It can causelife-threatening complications, in particular if the respiratory musclesare affected or if the autonomic nervous system is involved. Thisdisease is usually triggered by an infection. Acute inflammatorydemyelinating polyneuropathy (AIDP) is the most common subtype of thisdisease. Other subtypes of Guillain-Barré syndrome include MillerFischer syndrome, acute motor axonal neuropathy (Chinese paralyticsyndrome), acute motor sensory axonal neuropathy, acute panautonomicneuropathy, and Bickerstaff's brainstem encephalitis.

Hemorrhage: Bleeding or escape of blood from a vessel.

Hypoxia: The lack of oxygen supply to the tissues of the body below thenormal level.

Idiopathic inflammatory demyelinating disease (IIDD): A broad spectrumof central nervous system disorders that can usually be differentiatedon the basis of clinical, imaging, laboratory and pathological findings.Idiopathic inflammatory demyelinating diseases are sometimes known asborderline forms of multiple sclerosis. IIDD generally refers to acollection of multiple sclerosis variant diseases, including but notlimited to, optic-spinal MS, Devic's disease, ADEM, acute hemorrhagicleukoencephalitis, Balo concentric sclerosis, Schilder disease, Marburgmultiple sclerosis, tumefactive multiple sclerosis and solitarysclerosis.

Infantile Refsum disease: A peroxisome biogenesis disorder associatedwith deficiencies in the catabolism of very long chain fatty acids andbranched chain fatty acids (such as phytanic acid) and plasmalogenbiosynthesis. Infantile Refsum disease is a rare, autosomal recessivecongenital disorder, and one of three peroxisome biogenesis disordersthat belong to the Zellweger spectrum of peroxisome biogenesisdisorders.

Injury: Refers to any type of physical damage to cells, tissues, or thebody. In some cases, nervous system (e.g., CNS or PNS) injury results indemyelination and/or a demyelinating disease.

Ischemia: A vascular phenomenon in which a decrease in the blood supplyto a bodily organ, tissue, or part is caused, for instance, byconstriction or obstruction of one or more blood vessels. Ischemiasometimes results from vasoconstriction, thrombosis or embolism.Ischemia can lead to direct ischemic injury, tissue damage due to celldeath caused by reduced oxygen supply. In some cases, ischemia can leadto demyelination.

Krabbe disease: A rare, often fatal degenerative disorder that affectsthe myelin sheath of the nervous system. It is a form ofsphingolipidosis, as it involves dysfunctional metabolism ofsphingolipids. This condition is inherited in an autosomal recessivepattern. Krabbe disease is also known as globoid cell leukodystrophy orgalactosylceramide lipidosis.

Leber hereditary optic neuropathy: A mitochondrially inherited(transmitted from mother to offspring) degeneration of retinal ganglioncells (RGCs) and their axons that leads to an acute or subacute loss ofcentral vision; this affects predominantly young adult males.

Leukodystrophy: Refers to a group of diseases that affects the growth ordevelopment of the myelin sheath.

Leukoencephalopathy: Any of a group of diseases affecting the whitesubstance of the brain; can refer specifically to several diseasesincluding, for example, “leukoencephalopathy with vanishing whitematter” and “toxic leukoencephalopathy.” Leukoencephalopathies areleukodystrophy-like diseases.

Marburg multiple sclerosis: A condition in which the central nervoussystem has multiple demyelinating lesions with atypical characteristicsfor those of standard multiple sclerosis. This disease is a borderlineform of multiple sclerosis and is also known as tumefactive multiplesclerosis or fulminant multiple sclerosis. It is called tumefactivebecause the lesions are “tumor-like” and they mimic tumors clinically,radiologically and sometimes pathologically.

Marchiafava-Bignami disease: A progressive neurological diseasecharacterized by corpus callosum demyelination and necrosis andsubsequent atrophy. It is classically associated with chronicalcoholics.

Metachromatic leukodystrophy (MLD): A lysosomal storage disease that iscommonly listed in the family of leukodystrophies, as well as in thesphingolipidoses as it affects the metabolism of sphingolipids. MLD isdirectly caused by a deficiency of the enzyme arylsulfatase A.

Multifocal motor neuropathy (MMN): A progressively worsening conditionwhere muscles in the extremities gradually weaken. This disorder, amotor neuropathy syndrome, is sometimes mistaken for amyotrophic lateralsclerosis (ALS) because of the similarity in the clinical picture,especially if muscle fasciculations are present. MMN is usuallyasymmetric and is thought to be autoimmune.

Multiple sclerosis (MS): A slowly progressive CNS disease characterizedby disseminated patches of demyelination in the brain and spinal cord,resulting in multiple and varied neurological symptoms and signs,usually with remissions and exacerbation. The cause of MS is unknown butan immunological abnormality is suspected. An increased family incidencesuggests genetic susceptibility, and women are somewhat more oftenaffected than men. The symptoms of MS include weakness, lack ofcoordination, paresthesias, speech disturbances, and visualdisturbances, most commonly double vision. More specific signs andsymptoms depend on the location of the lesions and the severity anddestructiveness of the inflammatory and sclerotic processes.Relapsing-remitting multiple sclerosis (RRMS) is a clinical course of MSthat is characterized by clearly defined, acute attacks with full orpartial recovery and no disease progression between attacks.Secondary-progressive multiple sclerosis (SPMS) is a clinical course ofMS that initially is relapsing-remitting, and then becomes progressiveat a variable rate, possibly with an occasional relapse and minorremission. Primary-progressive multiple sclerosis (PPMS) presentsinitially in the progressive form. A clinically isolated syndrome is thefirst neurologic episode, which is caused by inflammation/demyelinationat one or more sites in the CNS. Progressive-relapsing multiplesclerosis (PRMS) is a rare form of MS (˜5%) characterized by a steadilyworsening disease state from onset, with acute relapses but noremissions.

Myelin: A lipid substance forming a sheath (known as the myelin sheath)around the axons of certain nerve fibers. Myelin is an electricalinsulator that serves to speed the conduction of nerve impulses in nervefibers. “Myelination” (also “myelinization”) refers to the developmentor formation of a myelin sheath around a nerve fiber. Similarly,“remyelination” (also, “remyelinization”) refers to the repair orreformation of the myelin sheath, such as following injury, exposure toa toxic agent, or an inflammatory response, or during the course of ademyelinating disease.

Neurodegenerative disease: Refers to any type of disease that ischaracterized by the progressive deterioration of the nervous system.

Neuropathy: A functional disturbance or pathological change in theperipheral nervous system. Axonal neuropathy refers to a disorderdisrupting the normal functioning of the axons.

Paraproteinemic demyelinating polyneuropathy: A type of peripheralneuropathy characterized by auto antibodies directed against myelinassociated glycoproteins (MAG). Anti-MAG antibodies inhibit theproduction of myelin, thereby leading to neuropathy.

Pelizaeus-Merzbacher disease (PMD): A rare central nervous systemdisorder in which coordination, motor abilities, and intellectualfunction are delayed to variable extents. The disease is one in a groupof genetic disorders collectively known as leukodystrophies.

Peroneal muscular atrophy (PMA): A genetically and clinicallyheterogeneous group of inherited disorders of the peripheral nervoussystem characterized by progressive loss of muscle tissue and touchsensation across various parts of the body. This disease is also knownas Charcot-Marie-Tooth disease (CMT), Charcot-Marie-Tooth neuropathy andhereditary motor and sensory neuropathy (HMSN).

Pharmaceutical composition: A composition containing sobetirome, or apharmaceutically acceptable salt thereof, formulated with apharmaceutically acceptable excipient, and manufactured or sold with theapproval of a governmental regulatory agency as part of a therapeuticregimen for the treatment of disease in a mammal. Pharmaceuticalcompositions can be formulated, for example, for oral administration inunit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup);for topical administration (e.g., as a cream, gel, lotion, or ointment);for intravenous administration (e.g., as a sterile solution free ofparticulate emboli and in a solvent system suitable for intravenoususe); or in any other formulation described herein.

Pharmaceutically acceptable salt: A salt of sobetirome which is, withinthe scope of sound medical judgment, suitable for use in contact withthe tissues of humans and animals without undue toxicity, irritation,allergic response and the like and are commensurate with a reasonablebenefit/risk ratio. Pharmaceutically acceptable salts are well known inthe art. For example, pharmaceutically acceptable salts are describedin: Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and inPharmaceutical Salts: Properties, Selection, and Use, (Eds. P. H. Stahland C. G. Wermuth), Wiley-VCH, 2008. The salts can be prepared in situduring the final isolation and purification of the compounds describedherein or separately by reacting the free carboxylic acid group with asuitable base. Representative alkali or alkaline earth metal saltsinclude sodium, lithium, potassium, calcium, magnesium, and the like, aswell as nontoxic ammonium, primary ammonium, secondary ammonium,tertiary ammonium, or quaternary ammonium cations, including, but notlimited to ammonium, tetramethylammonium, tetraethylammonium,methylammonium, dimethylammonium, trimethylammonium, triethylammonium,ethylammonium, and the like.

Pharmaceutically acceptable excipient (pharmaceutically acceptablecarrier): Any ingredient other than sobetirome, or a pharmaceuticallyacceptable salt thereof (e.g., a vehicle capable of suspending ordissolving the active compound) and having the properties of beingnontoxic and non-inflammatory in a patient. Excipients may include, forexample: antiadherents, antioxidants, binders, coatings, compressionaids, disintegrants, dyes (colors), emollients, emulsifiers, fillers(diluents), film formers or coatings, flavors, fragrances, glidants(flow enhancers), lubricants, preservatives, printing inks, sorbents,suspensing or dispersing agents, sweeteners, or waters of hydration.Exemplary excipients include, but are not limited to: butylatedhydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic),calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone,citric acid, crospovidone, cysteine, ethylcellulose, gelatin,hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose,magnesium stearate, maltitol, mannitol, methionine, methylcellulose,methyl paraben, microcrystalline cellulose, polyethylene glycol,polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben,retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch(corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide,vitamin A, vitamin E, vitamin C, and xylitol.

The pharmaceutically acceptable excipients or carriers useful for eachspecific mode of administration are described hereinbelow.

Preventing, treating or ameliorating a disease: “Preventing” refers to aprophylactic treatment or treatment that prevents one or more symptomsor conditions of a disease, disorder, or conditions described herein.Preventive treatment that includes administration of sobetirome, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition thereof, can be acute, short-term, or chronic. The dosesadministered may be varied during the course of preventative treatment.“Treating” refers to an approach for obtaining beneficial or desiredresults, e.g., clinical results. Beneficial or desired results caninclude, but are not limited to, alleviation or amelioration of one ormore symptoms or conditions; diminishment of extent of disease orcondition; stabilized (i.e., not worsening) state of disease, disorder,or condition; preventing spread of disease or condition; delay orslowing the progress of the disease or condition; amelioration orpalliation of the disease or condition; and remission (whether partialor total), whether detectable or undetectable. “Ameliorating(palliating)” a disease or condition means that the extent and/orundesirable clinical manifestations of the disease, disorder, orcondition are lessened and/or time course of the progression is slowedor lengthened, as compared to the extent or time course in the absenceof treatment.

Progressive multifocal leukoencephalopathy (PML): A rare and usuallyfatal viral disease that is characterized by progressive damage orinflammation of the white matter of the brain in multiple locations. PMLoccurs almost exclusively in people with severe immune deficiency. Thecause of PML is a type of polyomavirus called the JC virus. The virus iswidespread, with 86% of the general population presenting antibodies,but it usually remains latent, causing disease only when the immunesystem has been severely weakened. PML is a demyelinating disease, inwhich the myelin sheath covering the axons of nerve cells is graduallydestroyed, impairing the transmission of nerve impulses. The disease mayoccur in subjects (e.g., humans) with severe immune deficiency, such astransplant patients on immunosuppressive medications or those receivingcertain kinds of medications. For example, PML has been associated withadministration of rituximab (off-label use in the treatment of multiplesclerosis). It affects the white matter, which is mostly composed ofaxons from the outermost parts of the brain (cortex). Symptoms includeweakness or paralysis, vision loss, impaired speech, and cognitivedeterioration.

Sobetirome: A synthetic diarylmethane derivative that was investigatedclinically as a potential therapeutic for hypercholesterolemia (see U.S.Pat. No. 5,883,294, which is herein incorporated by reference). Othernames for sobetirome found in the literature and regulatory filingsinclude QRX-431 and GC-1.

Subject: An animal (e.g., a mammal, such as a human). A subject to betreated according to the methods described herein may be one who hasbeen diagnosed with a neurodegenerative disease involving demyelination,insufficient myelination, or under-development of a myelin sheath, e.g.,a subject diagnosed with multiple sclerosis or cerebral palsy, or one atrisk of developing the condition. Diagnosis may be performed by anymethod or technique known in the art. One skilled in the art willunderstand that a subject to be treated according to the presentdisclosure may have been subjected to standard tests or may have beenidentified, without examination, as one at risk due to the presence ofone or more risk factors associated with the disease or condition.

Therapeutically effective amount: A quantity of sobetirome, or apharmaceutically acceptable salt thereof, sufficient to achieve adesired effect in a subject, or in a cell, being treated withsobetirome. The effective amount of sobetirome depends on severalfactors, including, but not limited to the subject or cells beingtreated, and the manner of administration of the therapeuticcomposition. In some embodiments, a “therapeutically effective amount”of sobetirome, or a pharmaceutically acceptable salt thereof, is theamount sufficient to promote myelination in a subject. In otherembodiments, a “therapeutically effective amount” of sobetirome, or apharmaceutically acceptable salt thereof, is the amount sufficient toinhibit demyelination in a subject.

Transverse myelitis: A neurological disorder caused by an inflammatoryprocess of the grey and white matter of the spinal cord, leading toaxonal demyelination. Demyelination arises idiopathically followinginfections or vaccination, or due to multiple sclerosis. Symptomsinclude weakness and numbness of the limbs as well as motor, sensory,and sphincter deficits. Severe back pain may occur in some patients atthe onset of the disease.

Tropical spastic paraparesis (TSP): An infection of the spinal cord byhuman T-lymphotropic virus resulting in paraparesis, weakness of thelegs. TSP is also known as HTLV-associated myelopathy or chronicprogressive myelopathy. As the name suggests, this disease is mostcommon in tropical regions, including the Caribbean and Africa.

Van der Knaap disease: A form of hereditary CNS demyelinating disease.This disease is a type of leukodystrophy and is also known asmegalencephalic leukoencephalopathy with subcortical cysts (MLC).

X-linked adrenoleukodystrophy (X-ALD, ALD, or X-linked ALD): A rare,inherited metabolic disorder that leads to progressive brain damage,mental deterioration, failure of the adrenal glands, muscle spasms,blindness and eventually death. ALD is one disease in a group ofinherited disorders called leukodystrophies. Adrenoleukodystrophyprogressively damages myelin. X-linked ALD male patients may be dividedinto 7 phenotypes: childhood cerebral (progressive neurodegenerativedecline leading to a vegetative state), adolescent (similar to childhoodcerebral form but with a slower progression), adrenomyeloneuropathy(progressive neuropathy, paraparesis, may progress to cerebralinvolvement), adult cerebral (dementia, similar progression to childhoodcerebral form), olivo-ponto-cerebellar (cerebral and brain steminvolvement), Addison disease (adrenal insufficiency), asymptomatic (noclinical presentation, subclinical adrenal insufficiency, or AMNphenotype). X-linked ALD female patients may be divided into 5phenotypes: asymptomatic (no neurologic or adrenal involvement), mildmyelopathy, moderate to severe myelopathy (similar to male AMNphenotype), cerebral (progressive dementia and decline), and adrenal(primary adrenal insufficiency). X-linked ALD patients may progress fromone phenotype to another over the course of their life. ALD is alsoknown as Addison-Schilder disease or Siemerling-Creutzfeldt disease.

Zellweger syndrome: A rare congenital disorder, characterized by thereduction or absence of functional peroxisomes in the cells of anindividual. This disease is classified as a leukodystrophy and is one ofthree peroxisome biogenesis disorders that belong to the Zellwegerspectrum of peroxisome biogenesis disorders.

Unless otherwise explained, all technical and scientific terms usedherein have the same meaning as commonly understood by one of ordinaryskill in the art to which this disclosure belongs. The singular terms“a,” “an,” and “the” include plural referents unless context clearlyindicates otherwise. “Comprising A or B” means including A, or B, or Aand B. It is further to be understood that all base sizes or amino acidsizes, and all molecular weight or molecular mass values, given fornucleic acids or polypeptides are approximate, and are provided fordescription. Although methods and materials similar or equivalent tothose described herein can be used in the practice or testing of thepresent disclosure, suitable methods and materials are described below.In case of conflict, the present specification, including explanationsof terms, will control. In addition, the materials, methods, andexamples are illustrative only and not intended to be limiting.

III. Overview of Several Embodiments

Sobetirome, or a pharmaceutically acceptable salt thereof, provides aviable treatment for preventing and reversing demyelination and/orpromoting myelination in diseases or conditions associated withdemyelination, insufficient myelination, or underdevelopment of themyelin sheath.

The present disclosure features a method of treating a subject having orat risk of developing X-linked adrenoleukodystrophy by administering tothe subject in need thereof a therapeutically effective amount ofsobetirome or a pharmaceutically acceptable salt thereof.

The present disclosure also features a method of inhibiting accumulationof very-long chain fatty acids in a cell in a patient that has or is atrisk of developing X-linked adrenoleukodystrophy, by contacting theneuron with sobetirome, or a pharmaceutically acceptable salt thereof.

In some embodiments, the phenotype of X-linked adrenoleukodystrophy ischildhood cerebral, adolescent, adrenomyeloneuropathy, adult cerebral,olivo-ponto-cerebellar, Addison disease, or asymptomatic. In otherembodiments, the phenotype of X-linked adrenoleukodystrophy isasymptomatic, mild myelopathy, moderate to severe myelopathy (e.g.,adrenomyeloneuropathy), cerebral, and adrenal. In certain embodiments,the phenotype of X-linked adrenoleukodystrophy is cerebral. In otherembodiments, the phenotype of X-linked adrenoleukodystrophy ismyelopathy (e.g., moderate to severe myelopathy). In certain otherembodiments, the phenotype of X-linked adrenoleukodystrophy isasymptomatic. In yet other embodiments, the phenotype of X-linkedadrenoleukodystrophy is Addison disease. In certain embodiments, thephenotype of X-linked adrenoleukodystrophy is olivo-ponto-cerebellar.

The present disclosure features a method of treating a subject having orat risk of developing a disease or condition associated withdemyelination, insufficient myelination, or underdevelopment of myelinsheath. The method involves administration of a therapeuticallyeffective amount of sobetirome, or a pharmaceutically acceptable saltthereof.

The present disclosure features a method of inhibiting demyelination ofa neuron in a patient that has or is at risk of developing a disease orcondition associated with demyelination, insufficient myelination, orunderdevelopment of myelin sheath, by contacting the neuron withsobetirome, or a pharmaceutically acceptable salt thereof.

The present disclosure also features a method of promoting myelinationof a neuron in a patient that has or is at risk of developing a diseaseor condition associated with demyelination, insufficient myelination, orunderdevelopment of myelin sheath, by contacting the neuron withsobetirome, or a pharmaceutically acceptable salt thereof.

The disease or condition to be treated can be any disease or conditionassociated with demyelination, insufficient myelination orunderdevelopment of myelin sheath. In some embodiments, the disease orcondition is multiple sclerosis, a leukodystrophy, aleukoencephalopathy, an idiopathic inflammatory demyelinating disease,or Alzheimer's disease. In some examples in which the disease orcondition is multiple sclerosis, the multiple sclerosis isrelapsing-remitting multiple sclerosis, primary-progressive multiplesclerosis, secondary-progressive multiple sclerosis, orprogressive-relapsing multiple sclerosis.

In some embodiments, the disease or condition is central pontinemyelinolysis, acute disseminated encephalomyelitis, Balo concentricsclerosis, Marburg multiple sclerosis, tumefactive multiple sclerosis,diffuse myelinoclastic sclerosis, acute hemorrhagic leukoencephalitis,neuromyelitis optica, a chronic inflammatory demyelinatingpolyneuropathy, Leber hereditary optic neuropathy, multifocal motorneuropathy, paraproteinemic demyelinating polyneuropathy, tropicalspastic paraparesis, a Guillain-Barré syndrome, infantile Refsumdisease, adult Refsum disease 1, adult Refsum disease 2, Zellwegersyndrome, X-linked adrenoleukodystrophy (X-ALD), metachromaticleukodystrophy, Krabbe disease, Pelizaeus-Merzbacher disease, Canavandisease, Alexander disease, Binswanger's disease, peroneal muscularatrophy, cerebrotendineous xanthomatosis, leukoencephalopathy withvanishing white matter, toxic leukoencephalopathy, van der Knaapdisease, progressive multifocal leukoencephalopathy, Marchiafava-Bignamidisease or transverse myelitis.

In some examples, the Guillain-Barré syndrome is acute inflammatorydemyelinating polyneuropathy.

In some examples, the chronic inflammatory demyelinating polyneuropathyis multifocal acquired demyelinating sensory and motor neuropathy. Insome examples, the chronic inflammatory demyelinating polyneuropathy isinduced by HIV infection.

In some embodiments, the disease or condition is a chronic axonalneuropathy.

In some embodiments, the disease or condition results fromintraventricular hemorrhage, neonatal hypoxia, or acute hypoxemicrespiratory failure.

In some embodiments, the disease or condition is cerebral palsy.

In one embodiment, the disease or condition is not X-ALD. In anotherembodiment, the disease or condition is not multiple sclerosis. Inanother embodiment, the disease or condition is not cerebral palsy. Inanother embodiment, the disease or condition is not a leukodystrophy.

In some embodiments of the disclosed method, administration of thesobetirome or pharmaceutically acceptable salt thereof prevents ormitigates at least one symptom of the disease or condition. In someexamples, the symptom is a lack of sphincter control, erectiledysfunction, paraparesis, ataxia, adrenocortical insufficiency,progressive neuropathy, paresthesia, dysarthria, dysphagia, clonus, orany combination thereof.

In some embodiments, administration of the sobetirome orpharmaceutically acceptable salt thereof prevents or mitigates damage tocentral nervous system myelin, peripheral nervous system myelin, adrenalcortex, testicular Leydig cells, or any combination thereof.

In certain embodiments, sobetirome, or a pharmaceutically acceptablesalt thereof, is administered orally, parenterally, or topically. Inparticular embodiments, sobetirome, or a pharmaceutically acceptablesalt thereof, is administered orally. In certain embodiments,sobetirome, or a pharmaceutically acceptable salt thereof, isadministered enterally. In some embodiments, sobetirome, or apharmaceutically acceptable salt thereof, is administered buccally,sublingually, sublabially, or by inhalation. In other embodiments,sobetirome, or a pharmaceutically acceptable salt thereof, isadministered sublingually. In yet other embodiments, sobetirome, or apharmaceutically acceptable salt thereof, is administered parenterally.In particular embodiments, sobetirome, or a pharmaceutically acceptablesalt thereof, is administered intra-arterially, intravenously,intraventricularly, intramuscularly, subcutaneously, intraspinally,intraorbitally, intracranially or intrathecally.

In some embodiments, the sobetirome or pharmaceutically acceptable saltthereof is administered at a dose of about 1 μg to about 500 μg. In someexamples, the sobetirome or pharmaceutically acceptable salt thereof isadministered at a dose of about 10 μg to about 100 μg.

In some embodiments, the sobetirome or pharmaceutically acceptable saltthereof is administered daily.

In particular embodiments, the compound is administered to the subjectonce daily, twice daily, three times daily, once every two days, onceweekly, twice weekly, three times weekly, once biweekly, once monthly,or once bimonthly. In certain embodiments, the compound is administeredto the subject once daily. In other embodiments, the effective amount ismore than 30 μg (e.g., more than 50 μg, such as more than 100 μg). Insome embodiments, the effective amount is more than 30 μg (e.g., morethan 50 μg, such as more than 100 μg) daily. In certain embodiments, theeffective amount is more than 30 μg (e.g., more than 50 μg, such as morethan 100 μg) twice daily. In particular embodiments, the effectiveamount is more than 30 μg (e.g., more than 50 μg, such as more than 100μg) once weekly. In other embodiments, the effective amount is more than30 μg (e.g., more than 50 μg, such as more than 100 μg) twice weekly. Incertain embodiments, the effective amount is at least 30 μg (e.g., morethan 50 μg, such as more than 100 μg) three times weekly. In someembodiments, the effective amount is less than 1 mg (e.g., less than 500μg, such as less than 200 μg).

In some embodiments, the methods of the present disclosure involveadministering a unit dosage form containing from 10 μg to 100 μg ofsobetirome, or a pharmaceutically acceptable salt thereof, once, twiceor three times per day. In some embodiments, the methods of the presentdisclosure involve administering a unit dosage form containing from 10μg to 75 μg of sobetirome, or a pharmaceutically acceptable saltthereof, once, twice or three times per day. In other embodiments, themethods of the present disclosure involve administering a unit dosageform containing from 30 μg to 75 μg of sobetirome, or a pharmaceuticallyacceptable salt thereof, once, twice or three times per day. Inparticular embodiments, the methods of the present disclosure involveadministering a unit dosage form containing from 10 μg to 50 μg ofsobetirome, or a pharmaceutically acceptable salt thereof, once, twiceor three times per day. In yet other embodiments, the methods of thepresent disclosure involve administering a unit dosage form containingfrom 30 μg to 50 μg of sobetirome, or a pharmaceutically acceptable saltthereof, once, twice or three times per day. In still other embodiments,the methods of the present disclosure involve administering a unitdosage form containing from 50 μg to 75 μg of sobetirome, or apharmaceutically acceptable salt thereof, once, twice or three times perday.

The present disclosure also features a method of treating a patienthaving or at risk of developing multiple sclerosis by administering tothe patient a therapeutically effective amount of sobetirome, or apharmaceutically acceptable salt thereof. In one example, provided is amethod of treating a patient having or at risk of developing multiplesclerosis, comprising administering to the patient 1 mg/(kg of theweight of said patient)/day of sobetirome, or a pharmaceuticallyacceptable salt thereof.

Administration of sobetirome and pharmaceutically acceptable saltsthereof is further discussed in the section below.

IV. Administration of Sobetirome or Pharmaceutical Compositions Thereof

Sobetirome and pharmaceutically acceptable salts thereof can beadministered according to any suitable route of administration for thetreatment of a disease or condition associated with demyelination,insufficient myelination, or underdevelopment of myelin sheath. Forexample, standard routes of administration include oral, parenteral, ortopical routes of administration. In particular, the route ofadministration of sobetirome or a pharmaceutically acceptable saltthereof may be oral (e.g., enteral, buccal, sublingual, sublabial, or byinhalation). Parenteral route of administration of sobetirome, or apharmaceutical composition thereof, may be, e.g., intra-arterial,intravenous, intraventricular, intramuscular, subcutaneous, intraspinal,intraorbital, or intracranial. Topical route of administration may be,e.g., cutaneous, intranasal, or ophthalmic.

Pharmaceutical compositions comprising sobetirome have been described inthe art (see, e.g., U.S. Pat. No. 5,883,294, which is hereinincorporated by reference).

Sobetirome and pharmaceutically acceptable salts thereof that are to beadministered orally can be formulated as liquids, for example syrups,suspensions or emulsions, or as tablets, capsules or lozenges.

A liquid composition will generally include a suspension or solution ofsobetirome or pharmaceutically acceptable salt in a suitable liquidcarrier, for example ethanol, glycerine, sorbitol, non-aqueous solventsuch as polyethylene glycol, oils or water, with a suspending agent,preservative, surfactant, wetting agent, flavoring or coloring agent.Alternatively, a liquid formulation can be prepared from areconstitutable powder.

In some cases, a powder containing active compound, suspending agent,sucrose and a sweetener can be reconstituted with water to form asuspension; and a syrup can be prepared from a powder containing activeingredient, sucrose and a sweetener.

A composition in the form of a tablet can be prepared using any suitablepharmaceutical carrier(s) routinely used for preparing solidcompositions. Examples of such carriers include magnesium stearate,starch, lactose, sucrose, microcrystalline cellulose and binders, forexample polyvinylpyrrolidone. The tablet can also be provided with acolor film coating, or color included as part of the carrier(s). Inaddition, active compound can be formulated in a controlled releasedosage form as a tablet comprising a hydrophilic or hydrophobic matrix.

A composition in the form of a capsule can be prepared using routineencapsulation procedures, for example by incorporation of activecompound and excipients into a hard gelatin capsule. Alternatively, asemi-solid matrix of active compound and high molecular weightpolyethylene glycol can be prepared and filled into a hard gelatincapsule; or a solution of active compound in polyethylene glycol or asuspension in edible oil, for example liquid paraffin or fractionatedcoconut oil can be prepared and filled into a soft gelatin capsule.Sobetirome and pharmaceutically acceptable salts thereof to beadministered parenterally can be formulated, for example, forintramuscular or intravenous administration.

In some instances, a composition for intramuscular administrationcontains a suspension or solution of active ingredient in an oil, forexample arachis oil or sesame oil. A composition for intravenousadministration can include a sterile isotonic aqueous solutioncontaining, for example active ingredient, dextrose, sodium chloride, aco-solvent, for example polyethylene glycol and, optionally, a chelatingagent, for example ethylenediamine tetracetic acid and an anti-oxidant,for example, sodium metabisulphite. Alternatively, the solution can befreeze dried and then reconstituted with a suitable solvent just priorto administration.

Sobetirome and pharmaceutically acceptable salts thereof for rectaladministration can be formulated as suppositories. A typical suppositoryformulation will generally include active ingredient with a bindingand/or lubricating agent such as a gelatin or cocoa butter or other lowmelting vegetable or synthetic wax or fat.

Sobetirome and pharmaceutically acceptable salts thereof to beadministered topically can be formulated as transdermal compositions.Such compositions include, for example, a backing, active compoundreservoir, a control membrane, liner and contact adhesive.

Non-limiting examples of formulations for buccal, sublingual, and/orsublabial administration may be found in U.S. Pre-grant Publication No.2012/0058962, U.S. Pre-grant Publication No. 2013/0225626, U.S.Pre-grant Publication No. 2009/0117054, and U.S. Pat. No. 8,252,329; thedisclosure of each of which is incorporated herein by reference.

For buccal, sublingual, or sublabial administration, the compositionsmay take the form of tablets, lozenges, etc. formulated in aconventional manner, as described for oral dosage forms. In someembodiments, the formulation for buccal, sublingual, or sublabialadministration includes one or more of taste masking agents, enhancers,complexing agents, and other described above pharmaceutically acceptableexcipients and carriers.

Taste masking agents include, for example, taste receptor blockers,compounds which mask the chalkiness, grittiness, dryness, and/orastringent taste properties of an active compound, compounds whichreduce throat catch as well as compounds which add a flavor. A tastereceptor blocker used in the formulation of the present disclosure mayinclude Kyron T-134, a glycoprotein extract called miraculin from thefruit of the plant synsepalum dulcifcum, ethyl cellulose, hydroxypropylmethylcellulose, arginine, sodium carbonate, sodium bicarbonate,gustducin blockers and mixtures thereof. Compounds which mask thechalkiness, grittiness, dryness and/or astringent taste properties of anactive compound include those of a natural or synthetic fatty type orother flavorant such as cocoa, chocolate (e.g., mint chocolate), cocoabutter, milk fractions, vanillin butter fat, egg or egg white,peppermint oil, wintergreen oil, spearmint oil, and similar oils.Compounds which reduce throat catch include combinations of high and lowsolubility acids. For example, high solubility acids suitable for usehere include amino acids (e.g., alanine, arginine etc.), glutaric,ascorbic, malic, oxalic, tartaric, malonic, acetic, citric acids andmixtures thereof. Low solubility acids suitable for use include oleic,stearic and aspartic acids plus certain amino acids such as glutamicacid, glutamine, histidine, isoleucine, leucine, methionine,phenylalanine, serine, tryptophan, tyrosine, valine and fumaric acid.Actual amounts used will vary depending on the amount of throat catch orburn exhibited by the active used but will generally be in the range of1 to 40%. Flavoring agents include sweeteners and flavors. Examples ofsuitable sweeteners and flavors include mannitol, sorbitol, maltitol,lactitol, isomaltitol, erythritol, xylitol, sucrose, ammoniumglycyrrhizinate, mango aroma, black cherry aroma, sodium citrate,colloidal silicon dioxide, sucralose; zinc gluconate; ethyl maltitol;glycine; acesulfame-K; aspartame; saccharin; acesulfam K, neohesperidinDC, thaumatin, stevioside, fructose; xylitol; honey; honey extracts;corn syrup, golden syrup, misri, spray dried licorice root;glycerrhizine; dextrose; sodium gluconate; stevia powder; gluconodelta-lactone; ethyl vanillin; vanillin; normal and high-potencysweeteners or syrups or salts thereof and mixtures thereof. Otherexamples of appropriate flavoring agents include coffee extract, mint;lamiacea extracts; citrus extracts; almond oil; babassu oil; borage oil;blackcurrant seed oil; canola oil; castor oil; coconut oil; corn oil;cottonseed oil; evening primrose oil; grape seed oil; groundnut oil;mustard seed oil; olive oil; palm oil; palm kernel oil; peanut oil;grapeseed oil; sunflower oil; sesame oil; shark liver oil; soybean oil;hydrogenated castor oil; hydrogenated coconut oil; hydrogenated palmoil; hydrogenated soybean oil; hydrogenated vegetable oil; hydrogenatedcottonseed and castor oil; partially hydrogenated soybean oil; soy oil;glyceryl tricaproate; glyceryl tricaprylate; glyceryl tricaprate;glyceryl triundecanoate; glyceryl trilaurate; glyceryl trioleate;glyceryl trilinoleate; glyceryl trilinolenate; glyceryltricaprylate/caprate; glyceryl tricaprylate/caprate/laurate; glyceryltricaprylate/caprate/linoleate; glyceryl tricaprylate/caprate/stearate;saturated polyglycolized glycerides; linoleic glycerides;caprylic/capric glycerides; modified triglycerides; fractionatedtriglycerides; safrole, citric acid, d-limonene, malic acid, andphosphoric acid or salts and/or mixtures thereof.

Enhancers are the agents that increase membrane permeability and/orincrease the solubility of a particular active compound. Both issues canbe pivotal to the properties of the formulation. An enhancer may be achelator, a surfactant, a membrane-disrupting compound, a fatty or otheracid; a non-surfactant, such as an unsaturated cyclic urea. A chelatormay be, e.g., EDTA, citric acid, sodium salicylate, or amethoxysalicylate. A surfactant may be, e.g., sodium lauryl sulphate,polyoxyethylene, POE-9-laurylether, POE-20-cetylether, benzalkoniumchloride, 23-lauryl ether, cetylpyridinium chloride, cetyltrimethylammonium bromide, or an amphoteric or a cationic surfactant. Amembrane-disrupting compound may be, e.g., a powdered alcohol (such as,menthol) or a compound used as lipophilic enhancer. Fatty and otheracids include, e.g., oleic acid, capric acid, lauric acid, lauricacid/propylene glycol, methyloleate, yso-phosphatidylcholine, andphosphatidylcholine. Other enhancers that may be used in buccal,sublingual, and sublabial formulations of the present disclosureinclude, e.g., lysalbinic acid, glycosaminoglycans, aprotinin, azone,cyclodextrin, dextran sulfate, curcumin, menthol, polysorbate 80,sulfoxides, various alkyl glycosides, chitosan-4-thiobutylamide,chitosan-4-thiobutylamide/GSH, chitosan-cysteine, chitosan-(85% degreeN-deacetylation), poly(acrylic acid)-homocysteine,polycarbophil-cysteine, polycarbophil-cysteine/GSH,chitosan-4-thioethylamide/GSH, chitosan-4-thioglycholic acid, hyaluronicacid, propanolol hydrochloride, bile salts, sodium glycocholate, sodiumdeoxycholate, sodium taurocholate, sodium glycodeoxycholate, and sodiumtaurodeoxycholate.

Buffering materials can be both used to increase solubility and enhanceadsorption of active compounds. Examples of suitable buffering materialsor antacids suitable for use herein comprise any relatively watersoluble antacid acceptable to the Food & Drug Administration, such asaluminum carbonate, aluminum hydroxide (or as aluminum hydroxide-hexitolstabilized polymer, aluminum hydroxide-magnesium hydroxide co-dried gel,aluminum hydroxide-magnesium trisilicate codried gel, aluminumhydroxide-sucrose powder hydrated), aluminum phosphate, aluminumhydroxyl carbonate, dihydroxyaluminum sodium carbonate, aluminummagnesium glycinate, dihydroxyaluminum aminoacetate, dihydroxyaluminumaminoacetic acid, bismuth aluminate, bismuth carbonate, bismuthsubcarbonate, bismuth subgallate, bismuth subnitrate, calcium carbonate,calcium phosphate, hydrated magnesium aluminate activated sulfate,magnesium aluminate, magnesium aluminosilicates, magnesium carbonate,magnesium glycinate, magnesium hydroxide, magnesium oxide, and magnesiumtrisilicate, and/or mixtures thereof. Preferred buffering materials orantacids include aluminum hydroxide, calcium carbonate, magnesiumcarbonate and mixtures thereof, as well as magnesium hydroxide. Many ofthese compounds have the advantage of also being taste masking agentsparticularly useful for addressing throat catch.

The selection of the other excipients, such as permeation enhancers,disintegrants, masking agents, binders, flavors, sweeteners andtaste-masking agents, is specifically matched to the active depending onthe predetermined pharmacokinetic profile and/or organoleptic outcome.

Liquid drug formulations suitable for use with nebulizers and liquidspray devices and electrohydrodynamic (EHD) aerosol devices willtypically include sobetirome or a pharmaceutically acceptable saltthereof with a pharmaceutically acceptable carrier. Preferably, thepharmaceutically acceptable carrier is a liquid, e.g., alcohol, water,polyethylene glycol, or a perfluorocarbon. Optionally, another materialmay be added to alter the aerosol properties of the solution orsuspension. Desirably, this material is liquid, e.g., an alcohol,glycol, polyglycol, or a fatty acid. Other methods of formulating liquiddrug solutions or suspension suitable for use in aerosol devices areknown to those of skill in the art (see, e.g., U.S. Pat. Nos. 5,112,598and 5,556,611, each of which is herein incorporated by reference).

The dose and dosing schedule for administration of sobetirome (or apharmaceutically acceptable salt thereof) can vary and is determined inpart by the severity of the disease, and the age, weight and generalhealth of the patient. In some embodiments, the composition isadministered daily. In other embodiments the composition is administeredmore than once a day, such as twice a day, three time a day or fourtimes a day. In yet other embodiments, the composition is administeredless than once a day, such as every other day, every three days or oncea week.

In some embodiments, the dose of sobetirome (or a pharmaceuticallyacceptable salt thereof) is about 1 μg to about 500 μg (e.g., twicedaily, once daily, twice weekly, or once weekly), such as about 5 μg toabout 250 μg (e.g., twice daily, once daily, twice weekly, or onceweekly), about 10 μg to about 100 μg (e.g., twice daily, once daily,twice weekly, or once weekly), about 25 μg to about 75 μg (e.g., twicedaily, once daily, twice weekly, or once weekly), or about 50 μg toabout 100 μg (e.g., twice daily, once daily, twice weekly, or onceweekly). In particular examples, the dose of sobetirome (or apharmaceutically acceptable salt thereof) is about 1, 5, 10, 15, 20, 25,30, 40, 50, 60, 70, 75, 100, 125, 150, 200, 250, 300, 350, 400, 450 or500 μg (e.g., twice daily, once daily, twice weekly, or once weekly).

The following examples are provided to illustrate certain particularfeatures and/or embodiments. These examples should not be construed tolimit the disclosure to the particular features or embodimentsdescribed.

EXAMPLES Example 1: Use of Sobetirome for the Treatment of MultipleSclerosis (MS)

This example describes the finding that treatment with sobetiromedecreased demyelination in two different animal models of MS.

Chronic Demyelination Contributes to Disability and ProgressiveImpairment in MS

In MS, inflammatory cells induce multifocal demyelination and variableaxonal degeneration in the CNS, referred to as MS plaques. Consequently,people with MS develop a variety of neurologic deficits, includingparalysis, gait impairment, cognitive dysfunction, loss of sensation,and impaired vision. While remyelination occurs spontaneously as part ofthe natural repair process in MS, it is incomplete and tends to becomeineffective as the disease progresses. Failure of remyelination leads tochronically demyelinated axons that lose their ability to conduct axonpotentials normally resulting in neurologic dysfunction. Importantly,chronic demyelination may contribute to the pathogenesis of progressiveaxonal degeneration, which is a major cause of permanent disability.

Remyelination Occurs Early in MS but Fails as the Disease Progresses

Spontaneous remyelination occurs in MS and can be quite extensive. Morecommonly, remyelination occurs at the edges of typical demyelinatedplaques and tends to become less robust with longer disease duration.Why remyelination fails is uncertain. OPC are present near or indemyelinated plaques but for uncertain reasons do not differentiate intoOL and form myelin. It is possible that the demyelinated axons fail tosignal OPC properly. Another theory is that the astrocytic “scar” thatdevelops in chronic MS plaques inhibits OPC migration anddifferentiation, possibly through the presence of high molecular weighthyaluronic acid. It is also possible that activated microglia andmacrophages within and near the MS plaques release soluble factors thatinhibit OPC differentiation.

Animal Models for Studying Remyelination

Several animal models are in use to assess the effectiveness oftherapies to promote remyelination, including models that use a toxin(lysolecithin, ethidium bromide, or cuprizone) to induce demyelination;EAE; and Theiler's murine encephalomyelitis. In both the EAE andTheiler's models, demyelination is immune mediated. In this example, onetoxin model (lysolecithin) and one immune-mediated model (EAE) are usedto evaluate sobetirome.

Sobetirome Reduces Demyelination in the Lysolecithin Toxin Model ofFocal Demyelination

This study revealed that sobetirome can alter demyelination in thisfocal demyelination model (FIG. 1). Lysolecithin was injected into thecorpus callosum using stereotactic equipment at the x, y, z coordinatesof +1.000, +1.050, and +2.000 mm from the Bregma point using a beveledneedle with the bevel facing caudally. To minimize trauma, 2 μL of 2%lysolecithin or 2 μL of PBS was injected over four minutes using amicropump injector and the beveled needle was held in place for fiveminutes before withdrawal. Brains were harvested 8 days later and fixedin paraformaldehyde. Free-floating slices of 30 μm were sectioned with avibratome and stained with BlackGold® to detect myelin. Inlysolecithin-injected (but not PBS-injected) C57BL/6 mice, demyelinationwas observed in 6-8 serial sections in the corpus callosum (FIG. 1).

The initial experiment sought to determine how hypothyroidism,hyperthyroidism induced with high doses of T3, and administration ofsobetirome initiated before lysolecithin injection affected the extentof demyelination 8 days after lysolecithin injection. To inducehypothyroidism, mice were given 0.1% methimazole and 0.2% potassiumperchlorate in the drinking water for two weeks before lysolecithininjection; oral administration of these reagents inhibits the productionof thyroid hormone and induces hypothyroidism. Both T3 (0.4 mg/kg/day)and sobetirome (1.0 mg/kg/day) were administered daily by i.p. injectionstarting 7 days before and for 8 days after lysolecithin injection.Euthyroid control mice and hypothyroid mice received daily i.p.injections of vehicle for 7 days prior and 8 days after lysolecithininjection. Eight days after administration of lysolecithin (FIG. 1),mice receiving sobetirome and T3 had much smaller areas of demyelinationthan those receiving vehicle. Hypothyroid mice had much larger areas ofdemyelination that euthyroid mice. These initial experiments show thatthyroid status affects demyelination in the lysolecithin model, whichhas not been previously demonstrated, and that sobetirome decreasesdemyelination in this model.

Sobetirome Decreases Demyelination in EAE

This study was performed to assess the effects of sobetirome on EAE inC57BL/6 female mice immunized with MOG 35-55 peptide. Seventeen daysafter immunization, at peak of clinical disease, mice were randomized toreceive daily injections of sobetirome (1 mg/kg/day) or vehicle. After11 days of treatment, mice were euthanized and processed for histologicexamination. EAE clinical scores for the two groups did not differsignificantly. This is because the degree of inflammation within thespinal cords was similar between the two groups (Table 1) and much ofthe short term paralysis that occurs in EAE is secondary to effects ofinflammation on neural function. However, the lateral columns of thelumbosacral cord had significantly less demyelination in the micereceiving sobetirome compared with those receiving vehicle (p<0.01; FIG.2). Much of the effect appears related to protection of axons and myelinfrom damage (FIG. 3). Thus, sobetirome has a neuroprotective effect thatdecreases axonal damage and demyelination.

TABLE 1 Immunofluorescent staining of lumbosacral spinal cord sectionsstained for a macrophage marker (CD11b) and a T cell marker (CD4) %CD11b % CD4 ID Group # Staining Staining 1339 and 1340 Sobetirome 8 5.761.24 1342 Vehicle 4 3.89 1.01

Summary of Animal Model Data

Sobetirome decreased demyelination in the lysolecithin focaldemyelination model. This model is widely used to study mechanisms ofmyelin repair and to assess the therapeutic potential of drugs and othertherapies to promote remyelination in multiple sclerosis. Sobetiromealso decreased demyelination and axonal injury in experimentalautoimmune encephalomyelitis (EAE), the classic model of multiplesclerosis. These studies demonstrate that Sobetirome is effective inpromoting remyelination and serves as a neuroprotectant in multiplesclerosis.

Example 2: Sobetirome in an Animal Mode of Neonatal Hypoxia

Chronic neonatal hypoxia is a clinically relevant model of prematurebrain injury caused by insufficient gas exchange from poor lungdevelopment. This hypoxic state is a significant contributor to diffusewhite matter injury (DWMI), which is common in infants born prematurely.Chronic hypoxia can cause myelination abnormalities. A mouse model ofchronic hypoxia has been previously described (Scafidi et al., Naturedoi: 10.1038/nature12880 [Epub ahead of print], Dec. 25, 2013). Thismodel can be used to evaluate the effect of sobetirome onoligodendrocyte regeneration and remyelination following hypoxia.

Mice are randomly selected to undergo hypoxic rearing or to serve asnormoxic controls. Hypoxic mice are placed in a sealed chambermaintaining O₂ concentration at 10.5% by displacement with N₂ asdescribed previously (Raymond et al., J Neurosci 31:17864-17871, 2011;Bi et al., J Neurosci 31:9205-9221, 2011; Jablonska et al., J Neurosci32:14775-14793, 2012). Hypoxia is initiated at post-natal day (P)3 andcontinues for 8 days until P11. This time frame in rodent white matteroligodendrocyte development reproduces changes that occur at 23-40 weeksof gestation in the human brain (Back et al., J Neurosci 21:1302-1312,2001). Age- and strain-matched mice serve as normoxic controls.

Hypoxic mice and normoxic control mice are randomized to receive dailyinjections of sobetirome (1 mg/kg/day) or vehicle. In some examples,administration of sobetirome (or vehicle) is initiated at P11. In otherexamples, treatment is initiated at P3 or any time between P3 and P11.Multiple daily doses of sobetirome (and vehicle) can be administered.Following the desired course of treatment, mice are sacrificed and brainsections are prepared and processed to evaluate myelin thickness and thenumber of oligodendrocyte precursor cells in the white matter asdescribed (Scafidi et al., Nature doi: 10.1038/nature12880 [Epub aheadof print], Dec. 25, 2013).

All publications, patents, and patent applications mentioned in theabove specification are hereby incorporated by reference. Variousmodifications and variations of the described device and methods of useof the invention will be apparent to those skilled in the art withoutdeparting from the scope and spirit of the invention. Although theinvention has been described in connection with specific embodiments, itshould be understood that the invention as claimed should not be undulylimited to such specific embodiments. Indeed, various modifications ofthe described modes for carrying out the invention that are obvious tothose skilled in the art are intended to be within the scope of theinvention.

1-20. (canceled)
 21. A method of treating a subject having or at risk ofdeveloping acute hypoxemic respiratory failure, comprising administeringto the subject a therapeutically effective amount of sobetirome or apharmaceutically acceptable salt thereof.
 22. A method of treating asubject having or at risk of developing a disease or disorder followinga viral infection, comprising administering to the subject atherapeutically effective amount of sobetirome or a pharmaceuticallyacceptable salt thereof.
 23. The method of claim 22 wherein the diseaseor disorder is acute disseminated encephalomyelitis (ADEM).
 24. Themethod of claim 22 wherein the disease or disorder is progressivemultifocal leukoencephalopathy (PML).
 25. The method of claim 22 whereinthe disease or disorder is tropical spastic paraparesis (TSP).
 26. Themethod of claim 22 wherein the disease or disorder is chronicinflammatory demyelinating polyneuropathy.
 27. The method of claim 22wherein the disease or disorder is transverse myelitis.
 28. The methodof claim 22 wherein the disease or disorder is Guillain-Barre syndrome.